Absorption, distribution, metabolism and excretion

Prof. Ian Hughes, 9.83, i.e.hughes@leeds.ac.uk ‡ relevant to ALL drugs ‡ large research/development area ‡ frequent cause of failure of treatment ± failure of compliance ± failure to achieve effective level ± produce toxic effects ± drug interactions (*******) ‡ can enhance patient satisfaction with treatment ‡ understand different dosage forms available

Learning objectives
‡ To obtain a broad perspective over the field of ADME for drug molecules as a whole; ‡ To understand why ADME is important to drug action; ‡ To learn about the major pathways and mechanisms involved in ADME of drugs; ‡ To understand the importance of ADME to the dental practitioner; ‡ To obtain a basic knowledge about the quantitative aspects of ADME, pharmacokinetics

Overview - ADME
Most drugs : enter the body (by mouth or injection or«) - must cross barriers to entry (skin, gut wall, alviolar membrane«..) are distributed by the blood to the site of action - intra- or extra- cellular - cross barriers to distribution (capillaries, cell wall«.) - distribution affects concentration at site of action and sites of excretion and biotransformation are biotransformed perhaps to several different compounds by enzymes evolved to cope with natural materials - this may increase, decrease or change drug actions are excreted (by kidney or ««.) which removes them and/or their metabolites from the body Pharmacokinetics is the quantification of these processes

Some drugs work outside the body (barrier creams, some laxatives) but most must: ‡ enter the body: Given by: ENTERAL - oral, sublingual, buccal, rectal PARENTERAL sc, im, iv, it ‡ cross lipid barriers / cell walls: gut wall, capilliary wall, cell wall, blood brain barrier

---- get into the body and (after distribution) to reach the cellular target ----

tight junction) ‡ passage through the cell membrane ± diffuse through pore (very small. botulinum toxin in gut) ± diffusion through lipid of cell membrane (depends on AREA. saturable. L-DOPA at blood-brain barrier) ± pinocytosis (insulin in CNS.Passage through lipid membranes ‡ diffusion through gaps between cells (glomerulus = 68K. DIFFUSION GRADIENT. capillary 30K. LIPID SOLUBILITY) Ion channel Carrier Pinocytosis Diffusion . NB brain capillary . DIFFUSION COEFFICIENT. Fe in gut. use dependent) ± carrier mediated transport (specific.

9 = [ I ] Stomach pH = 2 0.4 99.Lipid solubility :weak acids and weak bases HA <==> H+ + A[ UI ] [I] B + HCl <==> BH+ + Cl[ UI ] [I] pKa=pH+log(HA/A-) ASPIRIN pKa = 4.9 = [ UI ] [ UI ] [ UI ] Aspirin is reasonably absorbed from stomach (fast action) Strychnine not absorbed until enters duodenum .4 99.5 (weak base) 100mg orally 0.1 = [ I ] Stomach pH = 2 Blood pH = 7.1 = [ UI ] Blood pH = 7.5 (weak acid) 100mg orally pKa=pH+log(BH+/B) STRYCHNINE pKa = 9.

inhalation. oral. different plasma peaks. sub-lingual (buccal). etc. for local or systemic effect . it. rectal.note patches Lungs. (usually local) Eye. enteric coated or slow release formulations absorption. sc.Routes of administration ‡ Enteral. Note iv infusors ‡ Parenteral. iv. Different rates of ‡ ‡ ‡ ‡ Skin. Note soluble. id. im. (usually local) . local or systemic effect? Vaginal.

Factors affecting oral absorption ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Disintegration of dosage form Dissolution of particles Chemical stability of drug Stability of drug to enzymes Motility and mixing in GI tract Presence and type of food Passage across GI tract wall Blood flow to GI tract Gastric emptying time FORMULATION .

v injection gives 100% bioavailability. Calculated from comparison of the area under the curve (AUC) relating plasma concentration to time for iv dosage compared with other route. Says nothing about effectiveness. .Bioavailability ‡ the proportion of the drug in a dosage form available to the body i.

Bioavailability Destroyed in gut Dose to systemic circulation Not absorbed Destroyed by gut wall Destroyed by liver .

Plasma concentration 60 50 40 30 20 Bioavailability (AUC)o / (AUC)iv i.v. route oral route Time (hours) 10 0 0 2 4 6 8 .

25mg) ng/ml 3.Bioequivalence: steady-state digoxin: Plasma digoxin different maker¶s products (0.5 2 1.5 0 1 2 3 4 5 6 7 8 Maker .5 3 2.5 1 0.

Sustained release preparations ‡ depot injections (oily. antibody-directed . GTN) ‡ pro-drugs ‡ liposomes Targeted drugs . particle size) ‡ multilayer tablets (enteric coated) ‡ sustained release capsules (resins) ‡ infusors (with or without sensors) ‡ skin patches (nicotine. viscous.

‡ Volume of distribution = V = D/Co plasma (3. brain) ‡ note::: plasma protein binding tissue sequestration ----. + special areas (foetus.5 l). intracellular fluid (50 l). extracellular fluid (14 l).but the body is not homogeneous.Overview .DISTRIBUTION The body is a container in which a drug is distributed by blood (different flow to different organs) .brings drug to target tissue and affects concentration at site of action/elimination----- . Note local delivery (asthma).

plasma expanders ‡ Extracellular fluid 14 litres. heparin. eye. tubocurarine. CSF. Tissue sequestration.5 litres.Distribution into body compartments ‡ Plasma 3. ethanol ‡ Transcellular small. pH partition . foetus (must pass tight junctions) Plasma protein binding. charged polar compounds ‡ Total body water 40 litres.

9 =1.1 0 -0. antilog 1.1.4 -0.5 = 31.1 0.6 0.6 logCt = logCo .303 TIME (hours) 5 10 15 20 log plasma concentration .6 1.Kel .5. t 2.

Alter plasma binding of drugs 1000 molecules 99. Effective TOXIC .9 1 % bound molecules free 90.0 100 100-fold increase in free pharmacologically active concentration at site of action.

can be changed by other drugs.METABOLISM ‡ Drug molecules are processed by enzymes evolved to cope with natural compounds ‡ Drug may have actions increased or decreased or changed ‡ Individual variation genetically determined ‡ May be several routes of metabolism ‡ May not be what terminates drug action ‡ May take place anywhere BUT liver is prime site ‡ Not constant . basic of many drug-drug interactions « metabolism is what the body does to the drug .Overview .

Biotransformation of drugs ‡ Mutations allowing de-toxification of natural toxic materials are advantageous and are selected ‡ Drugs are caught up in these established detoxification processes ‡ Drugs may converted to less toxic/effective materials more toxic/effective materials materials with different type of effect or toxicity .

plasma. gut wall and LIVER ‡ the liver is ideally placed to intercept natural ingested toxins (bypassed by injections etc) and has a major role in biotransformation .Sites of biotransformation ‡ where ever appropriate enzymes occur. kidney. lung.

The liver Hepatocytes portal venous blood systemic arterial blood smooth endoplasmic reticulum bile microsomes contain cytochrome P450 dependent mixed function oxidases venous blood .

hydrolysis (eg.couples group to existing (or phase I formed) conjugation site glucuronide (with glucuronic acid) OH O-SO3 sulphate others Phase I Phase II . by plasma esterases) others ‡ Phase II . reduction.Types of biotransformation reaction ‡ Any structural change in a drug molecule may change its activity ‡ Phase I . Microsomes (P450).changes drugs and creates site for phase II oxidation (adds O) eg.

different specificity .Cytochrome P450 dependent mixed function oxidases DRUG O2 microsome NADPH NADP+ METABOLITE =DRUG+O H+ WATER There are several different types of mixed function oxidase .

Genetic polymorphism in cytochrome P450 dependent mixed function oxidases CYP FOUR families 1-4 SIX sub-families A-F up to TWENTY isoenzymes 1-20 CYP3A4 : CYP2D6 : CYP2C9 : CYP2C19 :CYP2A6 CYP2D6*17 (Thr107Ile. Arg296Cys) Caucasian 0% Africans 6% Asian 51% .reduced affinity for substrates .

ug/ml 9 10 11 12 .No.8 mg/kg isoniazid orally 15 10 5 0 0 1 2 3 Isoniazid conc. of patients 25 20 Plasma conc in 267 patients after 9.

alters activity. made less lipid soluble so excreted .PHASE 1 reactions Hydroxylation -CH2CH3 Oxidation -CH2OH -CHO -CH2CH2OH -COOH + N-de-alkylation -N(CH3)2 . sulphate «.NHCH3 + CH3OH Oxidative deamination -CH2CHCH3 -CHCOCH3 | NH3 NH2 PHASE 2 reactions Conjugations with glucuronide.

sulphate with glutathione to give glutathione conjugates all tend to be less lipid soluble and therefore better excreted (less well reabsorbed) . epoxide.to give acetylated derivatives ‡ -halo.PHASE 2 reactions (not all in liver) CONJUGATIONS ‡ -OH. -CONH with glucuronic acid to give glucuronides ‡ -OH with sulphate to give sulphates ‡ -NH2. -CONH2. sulpha drugs with acetyl. -nitrate. aminoacids. -COOH. -SH.

uric acid production) ‡ enzymes for particular drugs (tyrosine hydroxylase. dopamine. dopa-decarboxylase etc) . noradrenaline. amines) ‡ Xanthene oxidase (6-mercaptopurine.Other (non-microsomal) reactions ‡ Hydrolysis in plasma by esterases (suxamethonium by cholinesterase) ‡ Alcohol and aldehyde dehydrogenase in cytosolic fraction of liver (ethanol) ‡ Monoamine oxidase in mitochondria (tyramine.

Phase I in action Imipramine 4-hydroxy imipramine (cardiotoxic) N CH2 CH2 N CH3 CH3 desmethyl imipramine (antidepressant) .

6h horse. 18h mouse. 13% Egyptians). fast = 95% Inuit. warfarin (bleeding) phenytoin (ataxia) Losartan (less cleared but less activated as well).Factors affecting biotransformation ‡ race (CYP2C9. 8h monkey. ‡ age (reduced in aged patients & children) ‡ sex (women slower ethanol metabilizers) ‡ species (phenylbutazone 3h rabbit. 13% Finns. 36h man). also fast and slow isoniazid acetylators. biotransformation route can change ‡ clinical or physiological condition ‡ other drug administration (induction (not CYP2D6 ) or inhibition) ‡ food (charcoal grill ++CYP1A)(grapefruit juice --CYP3A) ‡ first-pass (pre-systemic) metabolism . 50% Brits.

carbamazepine shorten action of drugs or increase effects of those biotransformed to active agents ‡ BLOCKERS acting on non-microsomal enzymes (MAOI. anticholinesterase drugs) .Inhibitors and inducers of microsomal enzymes ‡ INHIBITORS cimetidine prolongs action of drugs or inhibits action of those biotransformed to active agents (prodrugs) ‡ INDUCERS barbiturates.

The enterohepatic shunt Drug Bile duct Hydrolysis by beta glucuronidase Liver Bile formation Biotransformation. gall bladder glucuronide produced Portal circulation Gut .

‡ Tubular secretion active carrier process for cations and for anions. reduced by plasma protein binding. . Note effect of pH to make more of weak acid drug present in ionised form in alkaline pH therefore reabsorbed less and excreted faster.EXCRETION ‡ Urine is the main but NOT the only route. vica-versa for weak bases.Overview . ‡ Glomerular filtration allows drugs <25K MW to pass into urine. inhibited by probenicid. only a portion of plasma is filtered. ‡ Passive re-absorption of lipid soluble drugs back into the body across the tubule cells.

concentration of drug rises in tubule If lipid soluble drug moves down concentration gradient back into blood Re-absorption . filtrate 99% of GF is re-absorbed.Effect of lipid solubility and pH ionised drug is less lipid soluble Glomerular blood flow.

Special aspects of excretion ‡ lactating women in milk ‡ little excreted in faeces unless poor formulation or diarrhoea ‡ volatile agents (general anaesthetics) via lungs ‡ the entero-hepatic shunt glucuronic acid conjugates with MW >300 are increasingly excreted in bile. hydrolysis of say -OH conjugate by betaglucuronidase in gut will restore active drug which will be reabsorbed and produce an additional effect. .

Measure urine volume & concentration of drug conc in urine x vol per min = RENAL plasma concentration CLEARANCE If neither secreted nor reabsorbed then clearance = clearance of inulin = 120 ml/min If completely cleared by secretion then clearance = clearance of p-hippuric acid = renal blood flow = 700 ml/min . expired air.Pharmacokinetics ‡ Study of ADME on a quantitative basis In man study blood. faeces. urine.

Kel t logCt = logCo .303 y = c m x TIME (hours) . t 2.Kel .Plasma concentration 14 12 10 8 6 4 2 0 0 5 10 15 20 Ct = Co e-tKel lnCt = lnCo .

303 0.6 =1.9 log plasma concentration .6 1.1.Kel .4 5 10 TIME (hours) 15 20 -0.1 0.5 = 31.5.6 logCt = logCo .1 0 -0. t 2. antilog 1.

V directly from graph t1/2 = 0.693 / Kel (AUC)x / (AUC)iv .Pharmacokinetic parameters ‡ Volume of distribution ‡ Plasma clearance ‡ plasma half-life (t1/2) or ‡ Bioavailability V = DOSE / Co Cl = Kel .

steady state is reached. with acceptable variation at each dose and with a regimen which promotes compliance. ‡ At each dose the level will oscillate through a range ‡ The objective is to remain within the therapeutic window.Multiple dosing ‡ In a dental context some drugs are given as single doses. Many however are given as a course of therapy ‡ On multiple dosing plasma concentration will rise and fall with each dose and will increase until administration = elimination ie. .

plasma conc 6 5 4 3 2 1 0 0 5 10 toxic effective Cumulation and use of loading doses Time 15 20 25 .

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